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This is an interesting study that reinforces prior observations of altered regional brain iron levels in individuals with Alzheimer’s disease compared with age-matched controls (e.g. Tao et al., 2014). Significantly, this study presents new evidence that iron in a specific region of the cortex correlates with the rate of cognitive decline of the subjects. This postmortem evidence is important to inform and validate reported clinical measures of the relationship between cognitive decline and iron levels, determined indirectly via magnetic resonance Imaging (e.g. Du et al., 2018); it demonstrates how brain iron monitoring may be incorporated into disease progression monitoring of Alzheimer’s disease, to track cognitive change in tandem with physicochemical change in the tissues of the brain, and this is particularly important baseline information to evaluate the impact of treatments that affect iron metabolism.

As Ayton and colleagues discuss in this study, measures of total iron concentration alone do not prove a role for iron in disease progression; in this respect their work evidences correlation rather than causation. Indeed, from the perspective of Alzheimer’s disease as a proteinopathy, it is interesting to note that the present study reports only a weak correlation between iron levels and the hallmark plaques and tangles.

However, a critical factor that is frequently overlooked is that, with iron as an essential element in the brain, it is only when the tightly regulated trafficking and storage of iron is disrupted that iron might be expected to cause damage to cells and subsequent atrophy. Altered protein expression and/or function may impact bioavailability (e.g. Visanji et al., 2013). To understand the contribution of iron to neurodegeneration, it is important to evaluate the chemical form of the iron, identifying where it changes from its normal biological forms to more chemically reactive forms, creating potential to cause neuronal damage and subsequent atrophy.

Many previous studies have indicated that within tissues, the total iron concentration alone is not the critical factor. Instead, it is that iron associated with pathological brain features (i.e. the abnormal protein deposits—neuritic plaques and neurofibrillary tangles) is disproportionately in more chemically reactive forms. Of particular importance, there is strong evidence from in vitro, animal model, and human postmortem studies, including work from our group (e.g. Collingwood et al., 2008; Everett et al., 2014; Telling et al., 2017; Everett et al., 2018), that the interaction of peptides such as amyloid-β with iron is responsible for local elevations of chemically reactive iron. Indeed, the mechanisms involving iron that might propel cognitive decline, which Ayton and colleagues consider in their study, are consistent with iron chemistry being perturbed in this way. Therefore, a key finding: that within the regions studied there was only a weak correlation of total iron levels with the pathological burden in the brain tissue, is not unexpected and is consistent with prior work (e.g. House et al., 2008): It is likely to be the amount of reactive iron that is available to drive overproduction of radical species that is the crucial factor, rather than the total amount of iron at that site.

In summary, the findings of this study from Ayton and colleagues highlight the scope to use brain iron as an important biological marker of Alzheimer’s disease progression. The reported regional iron concentrations, and the weak correlation with pathological burden, reconfirm the value of differentiating the forms of iron present, to determine if there is evidence for disrupted iron bioavailability and chemistry to the detriment of the tissue.

Drs. Telling and Collingwood make excellent points. When measuring elemental composition of tissue in bulk, as we did, we do not achieve more discrimination than total metal levels. The values do not differentiate between iron species, microscopic location, and ligands, each of which is informative, as their previous work has shown. With postmortem tissue, as in our study, oxidation can induce artifacts of transition metal speciation, but nonetheless it is still possible to make meaningful comparisons for the chemical content of disease compared to healthy tissue with adequate controls. This is technically more laborious, but well worth investigating. We hope our current findings will stimulate more work in this area.

The article by Ayton et al. is pivotal to our understanding of iron’s role in Alzheimer’s disease (AD) pathology and dementia. This exciting work connects another important recent research on microRNA (miR-346) to the field. Let us try to iron out the kinks between AD, cognitive decline, iron, and miR-346.

It is beginning to dawn on us all that AD is not equivalent to the neuropathology associated with it. The separation of pathology from actual cognitive decline may need to be explained before AD can be reliably treated. If the net outcome in life quality and function is the same with or without pathology and depends on other factors, those "factors" may offer a more practical way to treat AD once it is diagnosed. After all, the field’s consensus is approaching the conclusion that it may be too late to treat AD based on pathology-associated molecules once it has advanced enough to be diagnosed. However, if the pathology sets up a necessary but not sufficient condition for actual AD to develop, traits or factors that then produce sufficiency could provide a way out of the “all diagnoses are too late” trap. Ayton et al. (in Ashley Bush’s lab) may have found, if not the escape hatch, at least an escape hatch. That is, deficiencies in Fe efflux could be a functional medical target at any stage of AD, not merely when the disorder is still undetectable.

In terms of Fe homeostasis, as a brain ages, it may accumulate fragility in the form of AD-associated pathology. However, so long as Fe efflux mechanisms are still vigorous, AD could possibly be avoided. If Fe efflux becomes too weak, the Fe interacts with a fragile brain and produces AD via several mechanisms as discussed in this forum. Even adding additional efflux after the fact could be insufficient to reverse or even halt the damage.

One important Fe efflux molecule is APP (Venkataramani et al., 2018; Rogers et al., 2016). It may be counterintuitive to suggest that an APP deficiency that occurs after AD pathology aggregates have formed could contribute to dementia, but some of our work in human brain tissue specimens at different AD stages suggests that changes in APP levels vary by Braak stage in a non-linear fashion (Long et al., 2012).

We cannot say ourselves what the levels of APP would be in human brains with no cognitive decline but strong AD pathology versus those with full-fledged AD (pathology plus dementia). Nevertheless, an apparent disruption of Fe metabolism associated with dementia suggests a possible role for APP dysregulation to do more than potentially make more raw material for Aβ.

Fe-based regulation of APP operates through at least two molecules, iron-response protein 1 (IRP1) (Venkataramani et al., 2018), and microRNA-346 (miR-346) (Long et al., 2019). These two operate antagonistically, with IRP1 suppressing and miR-346 enhancing translation, both at the same site in the APP mRNA 5'-UTR. It is also possible that the above interaction could stabilize the Fe efflux apparatus with other partners. Notably, levels of miR-346 are disrupted in AD brains (Long et al., 2019). We were, therefore, interested to see this unique and novel association between Fe and dementia in high-pathology brains. We hope that such a discovery is further used to investigate these brains’ concurrent levels of miR-346 and APP to test the hypothesis that disrupting the one disrupts the other in full AD (pathology plus dementia), and this disruption associates with Fe elevation and dementia in AD.